Project 3 Abstract Triple-Negative Breast Cancers (TNBC = negative by clinical assays for ER, PR and HER2) are among the most clinically challenging because of their inherent aggressive biology and lack of treatment options, which is typically limited to chemotherapy only. These tumors are more common in African American women and young women, and contribute to racial outcome disparity differences. To advance our knowledge of the biology of TNBC, we believe it critical to precisely define the biological entities that are present within this known heterogeneous group and to determine what is the driving biology. This should then allow us to identify robust biomarkers of response for the most relevant therapeutics that are, or might be, used in the breast cancer clinic for TNBC patients. TNBC are composed of multiple disease subtypes including Basal-like, Claudin- low/Mesenchymal, and Luminal-type tumors. We propose a divide-and-conquer approach where we will first use a biomarker strategy to segregate TNBCs into these more homogenous biological subtypes, and then target a key feature, or features, of each subtype in order to make advances for personalized medicine. For TNBC patients, chemotherapy treatment is still quite effective for many; therefore, we will continue our studies aimed at identifying the most chemotherapy responsive subset of TNBC patients. Many TNBC patients have tumors with sizable immune cell infiltrates as demonstrated by us and others. The presence of intra-tumor immune cells predict a better prognosis, and we hypothesize this feature might also predict the benefit of immune oncology directed agents as well. We propose to test this hypothesis and if successful, identify biomarkers for chemotherapy and immune therapy responsiveness in TNBC patients in order to deliver these drugs to the subset of patients whom would benefit the most.